With more than 15 million adult Americans meeting criteria for major depressive disorder each year, the management of depression is a central health care challenge. Inadequate response to initial antidepressant treatment is common and more than half of depressed patients require multiple sequential treatment steps to achieve remission of depressive symptoms. Despite modest efficacy, augmentation of antidepressants with second-generation antipsychotics (SGAs) is the most strongly supported and fastest growing pharmacological treatment alternative for treatment-resistant depression. Each year approximately 2 million outpatient visits for adult depression include a SGA. Yet the discovery of several serious SGA-associated adverse effects in other clinical populations, most strikingly a >50% increase in mortality risk in elderly dementia patients, raises critical questions about the safety of SGAs in depression as it is not known whether and to what extent these risks generalize to non-elderly adults who receive SGA augmentation for depression. Unfortunately, the combined experience of randomized clinical trials of SGAs for depression falls far short of sufficient power to detect a mortality risk in depression comparable to that observed in dementia. As a result, there is an urgent need for observational research to assess the safety of SGA augmentation in the treatment of adult depression. Using the most recent available 10 years of near national Medicaid data (2001-2010), the present study in approximately 80,000 non-elderly adults with depression and incomplete response to antidepressant monotherapy is the first to systematically examine the real-world safety of SGA augmentation. The proposed inferential analyses will be informed by a rigorous examination of the epidemiology of augmentation treatments in depression (Aim 1). All inferential analyses will employ an active comparator inception cohort design and use validated outcome measures. We will compare the incidence of rare, but serious, adverse events (all-cause mortality, sudden cardiac death, acute myocardial infarction, stroke, type 2 diabetes, pneumonia, venous thromboembolism) between patients initiating new episodes of SGA augmentation and those initiating antidepressant augmentation (Aim 2a). Following this class-level assessment, we will examine the safety of individual SGA augmentation strategies (Aim 2b). Finally, to facilitate personalized treatment, we will examine treatment effect heterogeneity by age group and baseline cardiovascular risk (Aim 3). Bias will be minimized by design (inception cohort, active comparator groups, careful restriction of the study population) and in the analysis (adjustment for a large number of demographic, clinical, and geographic characteristics using propensity score methods). Potential residual confounding will be examined in quantitative sensitivity analysis and instrumental variable analysis. The results will help inform clinical, regulatory, and health care policy efforts to improve the management of treatment-resistant depression and support or refute the need for large-scale prospective safety studies.